Bryan Johnson

Use of ultra pure nitric oxide generated by the reduction of nitrogen dioxide to reverse pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) has the capacity to selectively dilate pulmonary blood vessels, and thus enhance the matching of ventilation and perfusion, improve oxygenation and decrease pulmonary hypertension. However, existing approaches for the administration of inhaled NO are associated with the co-delivery of potentially toxic concentrations of nitrogen dioxide (NO2) due to the oxidation of NO in oxygen rich environments. We tested the ability of a novel methodology for generating highly purified NO through the reduction of NO2 by ascorbic acid to reverse pulmonary hypertension. In vitro testing demonstrated that the NO output of the novel device is ultrapure and free of NO2. An in vivo hypoxemic swine model of pulmonary hypertension was used to examine the dose response to NO in terms of pulmonary pressures and pulmonary vascular resistance. Pulmonary hypertension was induced by lowering inspired oxygen to 15% prior to treatment with inhaled ultra purified NO (1, 5, 20, and 80PPM). Hypoxemia increased mean pulmonary artery pressures and pulmonary vascular resistance. Inhaled ultra purified NO doses (down to 1PPM) show a marked reduction of hypoxemia-induced pulmonary vascular resistance. These experiments demonstrate a simple and robust method to generate purified inhaled NO that is devoid of NO2 and capable of reversing hypoxemia induced pulmonary hypertension.

Generation of purified nitric oxide from liquid N2O4 for the treatment of pulmonary hypertension in hypoxemic swine.

Inhaled nitric oxide (NO) selectively dilates pulmonary blood vessels, reduces pulmonary vascular resistance (PVR), and enhances ventilation-perfusion matching. However, existing modes of delivery for the treatment of chronic pulmonary hypertension are limited due to the bulk and heft of large tanks of compressed gas. We present a novel system for the generation of inhaled NO that is based on the initial heat-induced evaporation of liquid N2O4 into gas phase NO2 followed by the room temperature reduction to NO by an antioxidant, ascorbic acid cartridge just prior to inhalation. The biologic effects of NO generated from liquid N2O4 were compared with the effects of NO gas, on increased mean pulmonary artery pressure (mPAP) and PVR in a hypoxemic (FiO2 15%) swine model of pulmonary hypertension. We showed that NO concentration varied directly with the fixed cross sectional flow of the outflow aperture when studied at temperatures of 45, 47.5 and 50°C and was independent of the rate of heating. Liquid N2O4-sourced NO at 1, 5, and 20 ppm significantly reduced the elevated mPAP and PVR induced by experimental hypoxemia and was biologically indistinguishable from gas source NO in this model. These experiments show that it is feasible to generate highly purified NO gas from small volumes of liquid N2O4 at concentrations sufficient to lower mPAP and PVR in hypoxemic swine, and suggest that a miniaturized ambulatory system designed to generate biologically active NO from liquid N2O4 is achievable.